The focus of the optimization work on the HFETR fuel assembly is to achieve simultaneous irradiation of multiple irradiation test devices and ensure that all irradiation indicators can be met simultaneously. A complex fuel assembly co-design program for HFETR was established, which unifies and interfaces data between fuel management programs and thermal–hydraulic analysis programs, and displays key data of fuel assembly basic parameters and simulation parameters, and manages related data efficiently. A smart refueling model for the HFETR fuel assembly was built, which automatically initializes the fuel loading design according to the target setting and uses a hierarchical cross-layer strategy evolutionary algorithm to accelerate optimization iterations. The optimization of the fuel assembly scheme for various typical irradiation test devices (in-pile irradiation test devices and high-temperature high-pressure irradiation test devices) in the HFETR reactor core is carried out to meet the key irradiation targets (fuel core temperature, surface heat flux density, and line power density), based on the optimized results, it can be known that the final optimal solution has the irradiation device target parameters optimized to approach the target value, which can meet the irradiation task indicators better.